Abstract
A subset of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) benefit from pembrolizumab and nivolumab, but the majority of patients do not probably due to lack of activated cytotoxic CD8+ T-cells in their tumor tissues. Herein, we aim to investigate whether specific protein methyltransferases (PMTs) and demethylases (PDMTs) could play any roles in the CD8+ T-cell exclusion process in HPV-negative SCCHN. RNA sequencing data from the TCGA database were interrogated for HPV-negative SCCHN patients using a 10-gene chemokine signature that classifies SCCHN tissues into CD8+ T-cell inflamed and non-CD8+ T-cell inflamed phenotypes. Among 53 PMT/PDMT genes examined in the TCGA HPV-negative SCCHN database, expression levels of 15 PMT/PDMT genes were significantly negatively correlated with the chemokine signature score and CD8 mRNA expression levels. The expression level of each of these 15 PMT/PDMT genes showed significantly negative correlations with immune-active chemokines, as well as HLA class I and APM molecules. siRNA-mediated knockdown of a candidate PMT, SMYD3, led to upregulation of CXCL9, CXCL10, CXCL11 and TAP1 at mRNA and protein levels in HPV-negative SCCHN cell lines. These findings demonstrate that overexpression of some PMTs and PDMTs seems to be related with the non-CD8+ T-cell inflamed phenotype and may drive CD8+ T-cell exclusion in HPV-negative SCCHN. This study suggests that chromatin modifiers contribute to CD8+ T-cell exclusion and antigen presentation capacity of HPV-negative SCCHN, supporting that targeting of specific PMTs and/or PDMTs could enhance CD8+ T-cell infiltration and increase the proportion of patients that may benefit from immunotherapy.
Highlights
Squamous cell carcinoma of the head and neck (SCCHN) is a frequent cancer type with approximately50,000 patients diagnosed annually in the United States [1]
This study suggests that chromatin modifiers contribute to CD8+ T-cell exclusion and antigen presentation capacity of human papilloma virus (HPV)-negative SCCHN, supporting that targeting of specific protein methyltransferases (PMTs) and/or PDMTs could enhance CD8+ T-cell infiltration and increase the proportion of patients that may benefit from immunotherapy
Of the 53 PMT/PDMT genes examined, expression levels of 11 PMT and 4 PDMT genes were negatively correlated with the mean chemokine signature score (P < 0.05), which was defined as the arithmetic mean of normalized & log2-transformed expression of the chemokine genes (CCL2, CCL3, CCL4, CCL5, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13), calculated by/10
Summary
Squamous cell carcinoma of the head and neck (SCCHN) is a frequent cancer type with approximately50,000 patients diagnosed annually in the United States [1]. Patients with recurrent/metastatic (R/M) SCCHN treated with standard platinum-based chemotherapy regimens have poor prognosis with a median overall survival of approximately 10 months [3]. Pembrolizumab, a programmed-death-1 (PD1) monoclonal antibody, was approved as a second-line therapy for R/M SCCHN after failure to platinum-based chemotherapy [4]. Responses to pembrolizumab are as low as approximately 20% in PD-L1 positive tumors [4], 80% of the responders tend to have a durable response for more than 6 months, underlining the promise of immunotherapy as a novel therapeutic modality for SCCHN. While multiple clinical trials are currently being conducted to reduce or overcome immune suppressive mechanisms in the tumor microenvironment, the molecular factors involved in CD8+ T-cell exclusion and ineffective tumor-associated antigen presentation in SCCHN are still not well understood
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